long-lived Archives - Dr. Scott Rennie

There is a group of people in the southern Ecuadorian provinces of Loja and El Oro who almost never get cancer and almost never get diabetes. They are also, on average, about four feet tall.

Both facts have the same cause, and the story has been badly told for fifteen years. It gets written up as a longevity discovery. It is not one, and what it actually is turns out to be more interesting.

What the mutation does

Laron syndrome is a mutation in the growth hormone receptor. The pituitary makes growth hormone normally. The body cannot hear it. Since most of growth hormone’s effect on tissue runs through IGF-1, and IGF-1 production depends on that receptor working, people with the mutation have very low circulating IGF-1 from birth. They are short. Severely so, and untreated adults reach heights well below any normal range.

The Ecuadorian cluster is the largest known population with it, descended from a founder effect in a relatively isolated region.

The numbers that made people pay attention

Jaime Guevara-Aguirre followed roughly a hundred of these individuals for 22 years and published with Valter Longo’s group in Science Translational Medicine in 2011 (1).

Among the affected subjects: one nonlethal malignancy, and no cases of diabetes. Among their unaffected relatives, living in the same villages, eating the same food, drinking the same water: 17 percent cancer prevalence and 5 percent diabetes (1).

That is not a subtle effect. Not a hazard ratio you argue about. Essentially zero versus roughly one in six.

The metabolic picture explains the diabetes half. Fasting insulin in the affected group ran 1.4 µU/mL against 4.4 in relatives, and HOMA-IR was 0.34 against 0.96 (1). They were markedly more insulin sensitive, and this despite a high prevalence of obesity in the group, which is the detail that should make anyone who works in metabolic medicine sit up.

The cancer half is less settled. When the investigators treated human mammary epithelial cells with hydrogen peroxide in the presence of serum from affected subjects, they saw fewer DNA breaks and more apoptosis of damaged cells, along with reduced expression of RAS, PKA and TOR and increased SOD2 (1). Damaged cells being cleared rather than surviving to divide.

Here is the part that gets left out

They do not live longer.

People with Laron syndrome in this cohort live about as long as their unaffected siblings. The protection from cancer and diabetes is real and it does not translate into extra years, because the deaths come from elsewhere: accidents, alcohol-related causes, and convulsive disorders appear disproportionately (2).

So the honest summary is that this mutation removes two of the diseases that kill most of us, and the years get spent anyway. Which is a lesson about longevity research generally. Compressing morbidity and extending lifespan are different outcomes, and a study that shows one is routinely reported as showing the other.

A 2024 follow-up from the same group looked at cardiovascular risk in these subjects and found markers that were normal or better than their relatives (3), and earlier work has reported delayed age-related cognitive decline (3). The healthspan signal keeps holding up. The lifespan signal was never there.

Why this matters if you are not four feet tall

The obvious wrong conclusion is that low growth hormone is good and we should all have less of it. Nobody is proposing to give people this mutation.

The useful conclusion runs the other direction, at the anti-aging clinics selling growth hormone injections to men in their fifties. The GH and IGF-1 axis, pushed up, is the same axis that is pushed down in the population with almost no cancer. That does not prove supplemental growth hormone causes cancer in a 55-year-old, and I am not going to claim it does. It is a reason to ask what evidence exists that pushing the pathway the other way is safe over decades.

The other thread worth following is nutritional. The pathways involved here, IGF-1, TOR, PKA, are the same ones that respond to protein intake and to fasting, which is why Longo’s laboratory went from this cohort to fasting-mimicking diets. I have written elsewhere about what the fasting evidence does and does not support, and the short version is that the mechanism is well-motivated and the human outcome data is thinner than the enthusiasm.

The Bottom Line

A hundred or so people in southern Ecuador carry a growth hormone receptor mutation that appears to make them nearly immune to two of the most common chronic diseases in the world. One nonlethal cancer and zero diabetes in the affected group, against 17 percent and 5 percent in their own relatives. They do not live longer for it. That combination, better healthspan without longer lifespan, is the actual finding, and it is worth more than the version that gets headlined. If anyone offers you growth hormone as an anti-aging therapy, this cohort is the reason to ask what evidence they have that pushing that pathway up is safe.

Sources

1. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011;3(70):70ra13. PMID 21325617. https://pubmed.ncbi.nlm.nih.gov/21325617/

2. Guevara-Aguirre J, Guevara A, Palacios I, et al. Insights from the clinical phenotype of subjects with Laron syndrome in Ecuador. PMID 33047268. https://pubmed.ncbi.nlm.nih.gov/33047268/

3. Guevara-Aguirre J, Mishra A, Canepa M, et al. Normal or improved cardiovascular risk factors in IGF-I-deficient adults with growth hormone receptor deficiency. Med. 2024;5(7):816-825.e4. PMID 38677286. https://pubmed.ncbi.nlm.nih.gov/38677286/

Dr. Scott Rennie

Tag: long-lived

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